State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
Eur J Med Chem. 2010 Mar;45(3):1133-9. doi: 10.1016/j.ejmech.2009.12.018. Epub 2009 Dec 16.
The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB(1) receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB(1) receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.
本研究通过基于优势结构的方法鉴定了苯并哌嗪部分作为开发新型 CB(1) 受体调节剂的潜在支架。对最初的四个命中化合物进行有效的结构优化，得到了高质量的先导化合物系列，以化合物 6c 为代表。化合物 6c 是一种高效、选择性的 CB(1) 受体反向激动剂，能够减少饮食诱导肥胖的 Sprague-Dawley 大鼠的体重。讨论了基于优势结构文库的制备、从命中到先导的进展、先导系列的结构活性关系以及化合物 6c 的体外和体内活性。
